Continuous flow aminolysis under high temperature and pressure

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Process development for the synthesis of a second generation β-amyloid-cleaving enzyme (BACE1) inhibitor (1) is described. The lithiothiazole addition to the isoxazolene (5) under batch conditions was not scalable because of reaction gelling and anion instability. A continuous stirred-tank reactor flow process was developed and successfully executed on the 70 kg scale in multiple runs. In a head-to-head comparison between the continuous and batch processes, the former was clearly superior as it gave a higher yield (80 vs 63%) of the adduct (4) and better reaction control for handling the unstable lithiothiazole as a reaction intermediate. Subsequently, 4 underwent Pd-catalyzed amination with t-butyl carbamate, reductive cleavage of the N–O bond, thioamidine cyclization, and deprotection of the Boc group to provide hydropyranothiazine 2. The synthesis of 1 was completed by amidation with 5-(difluoromethoxy)picolinic acid and the successive deprotection of the benzamide group with either Silicycle-diamine or l-lysine.

Section: Results and Discussionmentioning

confidence: 99%

Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor—Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors

Barnhart

Dion

et al. 2021

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“…Based on previous internal experience in amination reactions, 200 °C was chosen to perform kinetic studies in order to determine optimal residence time (Figure ). A 1.5 M solution of 2 in THF mixed with 20 equiv of Me 2 NH (40 wt % aq) was used as single homogeneous solution to feed a 20 mL stainless steel (SS) coiled reactor at 900 psig.…”

Section: Results and Discussionmentioning

confidence: 99%

Hybrid Flow-Batch Model for the Efficient Synthesis of 2-(Dimethylamino)-6-methylpyridin-4-ol

Rincón¹,

Navarro

Nieves‐Remacha³

et al. 2021

A practical and scalable method for the synthesis of 2-(dimethylamino)-6-methylpyridin-4-ol is described. Despite its structural simplicity, the synthesis and isolation of this molecule in useful yields has proven to be challenging. A hybrid-flow (flow–batch–flow) mode approach was designed to circumvent issues associated with the safety and technical limitations of some of the steps in the process. The synthesis was successfully implemented to generate multigram quantities of a key intermediate for a drug candidate.

“…A continuous flow process was evaluated and showed promising results . It was found that a solvent of THF/water (4:2 vol) could provide a homogeneous mixture that was suitable for PFR.…”

Section: Results and Discussionmentioning

confidence: 99%

Developing a Multistep Continuous Manufacturing Process for (1R,2R)-2-Amino-1-methylcyclopentan-1-ol

Duan

Feng²,

Gonzalez³

et al. 2020

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A multistep continuous manufacturing process to synthesize (1R,2R)-2-amino-1-methylcyclopentan-1-ol (2) was developed. The step 1/2 flow process mitigated the safety hazard associated with high exothermicity during epoxidation, the epoxide-opening reaction, and the low onset of the epoxide intermediate. Process improvements included a hybrid plug flow reactor (PFR)/continuous stirred tank reactor (CSTR) reaction and a continuous quench/work-up process in step 1; a continuous reaction, extraction, washing, and thin-film distillation work-up in step 2; and a continuous trickle bed hydrogenation in step 3, which provided the desired product with high purity and high ee. The end-to-end continuous process provided significant advantages of cost-saving, minimization of manufacturing space and utilities, and reduction of the cycle time.